The identification of cancer biomarkers suitable for the early detection and diagnosis of cancer holds great promise to improve the clinical outcome of subjects. It is especially important for subjects presenting with vague or no symptoms or with tumors that are relatively inaccessible to physical examination. Despite considerable effort directed at early detection, few reliable and cost-effective screening tests have been developed that can diagnose cancer at an early stage.
As one example, ovarian cancer remains the sixth most common cancer in women worldwide, causing approximately 125,000 deaths annually (Sankaranarayanan & Ferlay, 2006). Most women with ovarian cancer are diagnosed at an advanced stage, with 75% diagnosed with extra-ovarian disease (Berek et al., 2003). In comparison with other cancers associated with women, 73% of endometrial cancers, 55% of breast cancers and 50% of cervical cancers are diagnosed with Stage I disease (Menon & Jacobs, 2000). While the 5-year survival of patients with Stage I ovarian cancer exceeds 90%, only 21% of advanced-stage ovarian cancer patients survive 5 years after initial diagnosis (Berek et al., 2003). Since long-term survival has not changed significantly in the past few decades, the best prospects for further improvement in ovarian cancer survival reside in early diagnosis (Menon & Jacobs, 2000).
The only biomarker currently approved for ovarian cancer detection is CA125 and its quantitation by ELISA has been the “gold standard” for detection of ovarian cancer since its introduction in 1983. Assessment of CA125 is typically used in disease management, both for disease detection as well as monitoring for disease recurrence; however, the use of CA125 is limited with regard to early stage cancer detection (sensitivity from 50-60%). CA125 quantitation is only approved for and consistently proven for remission monitoring. CA125 is neither sensitive nor specific for de novo ovarian cancer detection, since it is elevated in >50% of women with stage I disease, although it is elevated in more than 80% of patients with advanced stage ovarian cancer. CA125 has poor specificity, which is shown by its elevation in association with benign and malignant breast and colon disease, peritoneal irritants, and benign gynecologic diseases, among others.
New strategies that facilitate proteomic analysis by dramatically simplifying the pre-analytical sample separation and coupling with mass spectrometry (MS) have been introduced for biomarker discovery research. Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) has received much attention for its use in resolving proteins in biological specimens by binding to biochemically distinct protein chip arrays. In one technology, four serum proteins are examined by ELISA, while another technology uses mass spectrometry of seven specific serum components or general peptide patterns in patient serum to define the presence of cancer. SELDI-TOF-MS profiling has been successfully used to differentiate ovarian, breast, prostate, and liver cancer from controls.
SELDI-TOF-MS profiling of serum has been shown to be significantly better than the current standard serum biomarker CA125 at distinguishing patients with ovarian cancer from those with benign ovarian disease and from healthy controls. Studies have shown that the selection of a combination of multiple proteins resolved by SELDI-TOF-MS may have potential as a diagnostic approach. An effective screening test for ovarian cancer needs to achieve a high sensitivity and specificity and currently, different proteomic technologies as well as the computational analytic tools used to discern peaks generate different findings. These initial studies on SELDI-TOF-MS profiling insights are promising, and the concept is reproducible in a series of different backgrounds; however, translating this approach into a routine diagnostic test remains difficult.
It has been calculated that to be an effective screening test, an assay needs to achieve a minimum of 99.6% specificity. To achieve this level of specificity, multiple components of the tumor's characteristics will need to be incorporated into new diagnostic tests for effective detection because of the multifactorial nature of ovarian, as well as other cancers. A drawback of mass spectrometry techniques is that some samples of importance may be masked by more abundant proteins in the MS as well as in the analysis of the spectrometric output. Pre-purification by a number of techniques such as high-performance liquid chromatography and positive or negative selection through affinity binding can remove particular groups of proteins. The greatest challenge in most current mass spectrometry approaches is the dynamic range rather than sensitivity. While removal of prevalent proteins or peptides can greatly increase the informational content that can be acquired from particular samples, prevalent proteins such as albumin can function as carriers of protein subsets of diagnostic significance. Additional studies with larger samples sizes and careful blinding of the independent validation sets are needed before any consideration of application of this platform for screening for ovarian cancer or any other indication should be considered.
Thus, a need persists for the development of improved biomarkers in nearly all cancers and other disorders, including the increased risk for adverse pregnancy outcomes. Blood-based assays remain an attractive goal due to the availability and ease of sample collection. Earlier definitive diagnosis of cancer and increased risk for adverse pregnancy outcomes would facilitate earlier and potentially more effective treatment of patients. As such, there is an unmet need for new biomarkers that individually, or in combination with other biomarkers or diagnostic modalities, deliver the required sensitivity and specificity for early detection and prognosis of cancer and adverse pregnancy outcomes. In particular, simple tests for cancer biomarkers and adverse pregnancy outcomes performed on readily-accessible biological fluids are needed.